Wound healing involves a complex but orderly sequence of cellular events that culminates in the restoration of structural integrity of tissue. The orderly influx of inflammatory cells, proliferation of stromal elements, in-growth of blood vessels, and production of an extracellular matrix are essential for rapid and efficient healing. Maximum tissue strength is achieved through the regulated remodeling and maturation of the extracellular matrix. Tissue repair is regulated in part by cells at the wound site that control the local production of growth factors, including transforming growth factor beta. Wound healing begins with a repair cascade which culminates in the formation of new granulation tissue.
Cutaneous ulcers are a common, chronic problem in dogs and are primarily developed as pressure (decubital) sores. In addition to causing pain and discomfort to the animal, and predisposing the animal to superficial and chronic infection, significant costs are associated with the treatment of the animal. Certain breeds of dogs may be especially predisposed to decubital ulcers due to neurologic conditions associated with the breed. These include Dachshunds as a result of intervertebral disc herniation and large breeds such as Doberman Pinschers and Great Danes which are predisposed to cervical vertebral instability. Furthermore, any condition which results in paraplegia or tetraplegia can result in pressure ulcers.
Chronic ulcers may also arise as a result of chronic steroid therapy for autoimmune disease or atopic dermatitis as well as chemotherapy for cancer. These conditions and their treatment regimens may impair the normal wound healing process and often result in chronic ulcers in the debilitated animal. While the etiology of pressure sores or ulcers resulting from chronic steroid or chemotherapy may be different, the underlying manifestation is the lack of formation of granulation tissue and re-epithelialization of the defect. In dogs, the acral lick granuloma (acral lick dermatitis) can occur as a result of excessive licking which gradually wears away the cutaneous layers. Dehiscence wounds form as a result of failed surgical sutures. Depending on the health and background of the patient, these cutaneous open wounds and ulcers can persist chronically for extended periods of time. Each of these types of cutaneous open wounds and ulcers results in considerable discomfort to the patient and presents a continuing opportunity for even more serious infections or complications to occur. In addition to these common cutaneous open wounds and ulcers, a variety of other skin defects are known to occur in both animals and humans, including lacerations, perforations, wounds which are traumatic in origin, venous stasis ulcers, and other types of lesions.
These types of wounds also occur in other vertebrates such as birds and reptiles. The fundamental pathogenesis of wounds and processes for wound healing is similar for all vertebrates, and therefore the person of ordinary skill will realize that the methods and compositions of the present invention are useful for treating chronic wounds and ulcers in all vertebrates.
Starch is a polymer of carbohydrate moieties which are arranged in a macromolecular structure. Persons of ordinary skill in the art understand that the term "hetastarch" is meant to describe carbohydrate moieties that have been esterified so that several of the hydroxyl groups of the D-glucopyranose units of the starch polymer have been converted into hydroxyethyl groups. Hetastarch is commonly utilized in preparations of plasma volume expanders to avoid the potentially fatal shock which can result from severe blood loss, particularly in cases where the treated patient has experienced a large volume of blood loss. These hetastarch compositions are considered a safer alternative to blood products as their use avoids the possibility of transmitting blood-borne diseases. They are also useful for treating patients who object to blood products for resuscitation and when donor blood is unavailable or available in insufficient quantities. Hetastarch compositions are also significantly less expensive than donated blood.
Hetastarch is also known in the art as hydroxyethylated amylopectin, hydroxyethyl starch, or generally as a branched chain polymeric .alpha.-D-glucan. The term hetastarch as used herein is meant to include these and any other terms known in the art as describing branched chain polymeric .alpha.-D-glucans which have been esterified so that several of the hydroxyl groups of the D-glucopyranose units of the starch polymer have been converted into hydroxyethyl groups.
The present invention resulted from the unexpected discovery that compositions containing hetastarch are also useful for promoting the healing of cutaneous open wounds and ulcers. In a recent study it was unexpectedly found that chronic open wounds and ulcers in dogs treated with a composition of hetastarch healed as well as chronic open wounds and ulcers treated with a known biochemical wound healing agent.